This proposed K08 Mentored Career Development Award will enable me to develop into an established and independent researcher with expertise on the role of ion channels in smoking related lung disease. I am a fully trained pulmonary and critical care physician as well as a basic and translational researcher with a long-term goal of understanding the implications of ion channel dysfunction in smoking related lung disease. However, further career development and research training is necessary for me to reach this goal. I have a long- standing, productive relationship with my mentor, Dr. Jeanine D'Armiento, a well-established researcher in matrix metalloproteinase biology and smoke related lung disease. In collaboration with Dr. Andrew Marks, co- mentor of this proposal, and Dr. Steven Marx, a member of my advisory committee, we recently demonstrated that activation of large conductance, voltage and Ca2+ activated potassium (BK) channels with the compound rottlerin reduces airway hyper responsiveness in two murine models of asthma. The present proposal extends this successful collaboration and examines alterations in BK channel and ryanodine receptor (RyR) activity in smoke exposure conditions. We have identified post-translational modifications of RyR2 and potential BK channel mediated alterations in matrix metalloproteinase expression in smoke exposure, and seek to determine the mechanisms underlying these interesting findings. Through the use of unique transgenic and knock-in mice, we will explore the role of BK channels and implications of post-transcriptional RyR2 modifications in destructive lung injury. I will work with a multidisciplinary advisory committee o established NIH investigators (Dr. D'Armiento, Dr. Marks, Dr. Marx, Dr. Charles Emala and Dr. Jahar Bhattacharya) to help me attain the goals of (1) utilizing unique animal models to understand the mechanisms of lung destruction; (2) obtaining training in electrophysiology methods to investigate smoke-induced cellular dysfunction; and (3) learning skills for research presentations, publications and effective grant writing for obtaining independent funding. I will use the skills acquired during this mentored research project to further my understanding of ion channels in destructive lung disease in the hope of identifying novel targets for new therapies.